Trifluoromethyl substituted phenoxazines



Unitfid State m Qfi c Arte:

2,947,147 TRIFLUOROMETHYL SUBSTITUTED PHENOX'AZINES Pen eme, Ro lyn, 1 's.; assi ns: to Sniith- Kline & French Laboratories; Philadelphia, Pa., a corporation of Pennsylvania w 7 N6 Drawing File-a June is; 1'95"9, seeNb. 18 18,509 is Claims of. 2 60-2 44) This invention relates to novel IO-(aminoalkyD-Z-trifluoromethylphenozgazines having-utility as pharmacodynamic agents. This invention also relates tolthe novel Z-trifluoromethylphenoxazine of; use as an intermediate in the preparation of the (aminoalkyl) phenoxazine derivatives. x I The 'novel lo-(aminoalkyl)-2-trifluoromethylphenoxaz ine compounds of this invention have] particular utility as sedatives, tranquilizers and antiemetics, and have a minimumof side-eifectsI More specifically, the novel"10=(aminoallryl) 2-trifiuoromethylphenoxazine compounds of this invention are represented by the following structure:

FORMULAZI 7 CF: N Jam-ou-om-z' on or Condensation alkylenel-piperaiiriyl such as dimethylor diethylcarbamyl; and R5 represents hydrogen or methyl, Preferred compounds of this invention are represented by Formula II above when Z represents N-methylpiperazinyl, N- (a: hydroxyethyD-piperazinyl, N-(w-acetoxyethyl) -piperaziny l, N- w-lrydroxyethoxyethyl) -piperazinyl, N (w-hydroxyethoxyethoxyethyl)-piperazinyl, N-(w-canbamyloxyethyU-piperaiiny1 or N-(o-dimethylcarbamyloxyethyl)-piperazinyl; and Ii -represents hydrogen or methyl; preferably hydrogen; in. particular 10-[3-( N- hydroxyethylpiperazinyl) -'-p'ropy1] 2 trifluoromethylphenoxazine.

By the term aminoalkyf where usedherein aloneor in combination with other terms, moieties such as dialky'larninoalkyl' and piper aiin yl-r or substituted piperazinylalkyla-re indicated; The term N-alkylpiperazinyl represents a piperazi-nyl ring substituted on the free nitrogen with an aliphatic group having not more than -4 carbon atoms. The term alkylene represents aliphatic groups of from Z to'4 carbon atoms. The term acyl represents groups derived fromorganic hydrocarbon carboxylic acids such 'asi'al-kanoyl havingfrom 2 to 4 carbon atoms l';l j"'s invention also includes salts ofithe above defined bases formed with pharmaceutically acceptable nontoxic organic and inorganic acids. Such-sa1ts are easily prepared lby methods knownto the art. The base is' reacted with either the calculated amount of organic or inorganic when '2" represents dimethylamino, diethyIaminQ,'-1N,-liyliydr'oxythoiiyethoxyethyl)-piperazinyl,, N-twwarbamyracid i'n'f aqueous miscible solvent, such asacetone or ethanol, with isolation of the salt by concentration and cooling or .an 'excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, pamoic, succin ic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, glucpnicgglacti'c, mane; mand'elie; cinnanii'c,'-*-'citracohi, 1 as; partrc, stearic, palniitic, ita'co'rii'c g'l-ycolic, pganii'nobenzoic, glutarnie, benzenesulfonie and theophylline acetic acids as iv'ellas' with the 8ghalothfeophyllines', for example, 8- h'romotheophylline, Exemplary" of such inorganic salts are thosewith hydrochloric, hydrobrornic, sulfuric, sulfamiqphosphoric and nitric'acids'. Of course these salts ma also be prepared by theclassical, method of double decomposition of appropriate salts which well knowii toithe art. 7

j The novel Zl-trifiuorbinethylphenoxazine, used as an intern'iediate to prepar'ethe' lo-taminoa'lkyl)ephenoxazines described'in Formula I as is disclosed hereinafter, isflp'repared by the followingisynthetic route:

"Reduction Hydrolysis CF13" "C1511 N I I /,R| 'HPCBFCHz-N J when one of lorfY triiiuoroinethyL and ltheother 1' 3 v either in the 4 position of the nitrohalobenzene or in the which distills azeotropically with water. Removal of 4 position of the guaiacol to form the correspondingly the water from the reaction mixture as it is formed entrifluoromethyl substituted 2-methoxy-2-nitrodiphenyl hances yields. ether. The reactants are heated, preferably at reflux, in The N-formyl derivative which is formed by the cyclithe presence of water and a condensing agent, for exam- 5 zation reaction is hydrolyzedpreferably with alkali such ple, an alkali metal hydroxide such as sodium hydroxide as with dilute sodium or potassium hydroxide solution or potassium hydroxide. The thus formed trifluoroto give the 2-trifluoromethylphenoxazine intermediate. methyl substituted-2'-methoxy-2-nitrodiphenyl ether is re- In general, it is preferred to carry out the reaction withduced preferably employing Raney nickel-hydrazine hyout isolating the N-formyl derivative. The process out: drate in ethanol or by catalytic hydrogenation, for inlined above is described more fully in a co-pending apstance with platinum oxide catalyst. plication, Serial No. 813,082, filed May 14, 1959.

The resulting corresponding trifluoromethyl substituted- To form the compounds of Formula I, 2-trifluoro- 2'-methoxy-2-amidodiphenyl ether is then hydrolyzed to methylphenoxazine prepared as described above is alkylthe 2-amino-2'-hydroxydiphenyl ether preferably by ated with a reactive aminoalkyl ester such as a halide, heating in the presence of 48% hydrobromic acid or by preferably chloride or bromide, or an arylsulfonate such heating with hydrochloric acid in a closed system such as p-tosylate or phenylsulfonate in a suitable inert aroas a sealed tube, the temperature ofthe reaction in both matic solvent such as benzene, xylene or toluene, in which cases being maintained in the range of from about 120 at least one of the reactants must be soluble. A suit- C.- to about 140 C. The substituted 2r-amino-2'-hyable acid-binding agent may be included such as an alkali droxydiphenyl ether is then cyclized to the desired 2- metal amide, preferably sodium amide or potassium trifluoromethylphenoxazine by heating the amino comamide; an alkali metal hydride, for example, sodium or pound with a mineral acid, for example, sulfuric, or a potassium hydride, and preferably sodium hydride; an hydrohalic acid such as hydrobromic or hydrochloric alkali metal hydroxide, for example, sodium or potasacid, preferably in a closed system such as in a Carius sium hydroxide and preferably potassium hydroxide or tube, at from about 180 C. to 220 C. until the cyclizaan alkali metal aryl or alkyl compound, preferably tion'is complete, normally from 4 to 72 hours. 7 phenyl sodium or octyl sodium.

Alternatively, the novel Z-trifluoromethylphenoxazine If an acid addition salt of the reactive aminoalkyl intermediate is prepared by the following synthetic route: ester is used, a corresponding increase'in the amount of one 0H0 7 when X is a reactive halogen f at i weight greater acid-binding agent must also be used. The preferred than 3 6, preferably bromine; nd one of W 0 Y is trimethod of alkylation, however, is to react the Z-trifluorofluoromethyl, and the other is hydrogen. In carrying out methylp with an aminoalkyl chloride this process, a Z-h'alophenol is condensed with a 2-chloromide with a slight excess of sodium or potassium amide nitrobenzene and the resulting 2'-halo-2-nitrodiphenyl in r i g e n or toluene f r m 30 mi to ether is reduced chemically or catalytically to give the 24 1101115, Preferably two to eight hours- 2-'amino2'-halodiphenyl ether. The Z-amino diphenyl The -p p y y P ether derivative is N,formylated, preferably as a melt, zines are prepared advantageously by alkylating 2-triwith a concentrated aqueous solution of formic acid such r me hy p with an w-haloalkylpiperazihfi as from to 98% formic acid.' Advantageously com- 50 With e free y g 0f the p p y moiety P mercial formic acid solution is used, about 85to 95%. cte by, for example, a benzyl, carbobenzoxy, carbeth- The formylation in aqueous solution is advantageously oxy or formyl group. The N-protective group is then carried out at temperatures of from about 140-180" C., r s h as y mild hy r y The resulting preferably about 160 C. e V f w-piperazinylalkyl phenoxazine may be alkylated further The resulting 2-formamido-2'-halodiphenyl ether is to form various substituted piperazinyl derivatives of this cyclized by heating with one molar equivalent, or prefinvention as set forth specifically in Formula II. Such erably an excess, of an alkali earth carbonate, for exmethods of alkylation are by a reactive ester such as an ample sodium bicarbonate, potassium carbonate or so" alkyl halide, an aryl sulfonate or a halo substituted drum carbonate, preferably in the presence of a copper alcohol, for example ethylene chlorohydrin, w-bromocatalyst such as copper bronze, copper powder or a" cop- 1 2-(2'-hrOII10eth0Xy)-ethah01, in the Presence per salt, preferably cupric carbonate. The reaction is of an acid-binding agent in inert solution such as benzene; run in a high boiling solvent in which the reactants are by reaction with an alkylene oxide such as ethylene oxide at least partially soluble such as a liquid tertiary acid illalcohol y reduction of a N-acyl Compound Such amide, for example N-dimethylformamide, N-dirnethylas reduction of the N-acyl analogue with a bimetallic acetamide, or an aromatic solvent suchas benzene, xylhydride such as lithium aluminum hydride. In addition, one or toluene. l0-(N'-alkyl-N-piperazinylalkyl)-2-trifluoromethylphenox- The cyclization reaction is run at elevated temperaaziues having a terminal group on the N-alkyl moiety turessuch as from about C. to about 250 0., adcapable of undergoing reaction are optionally reacted vantageously from about C. to C., for profurther in the presence of an acid-binding agent to give longed periods such as from 1 0.to 48 hours. The 70 the -corresponding -N'-substituted-alkyl derivatives. As reaction is usually run at the boiling point of the reaction examples of terminal groups on the N-alkyl moiety which m xture. 7 r 7 can-be reacted further, an w-hydroxyalkylene is reacted A particularly advantageous modification of this procwith anester such as an acyl halide in the presence of an ess is to employ a high boiling aromatic solvent such as, acid-binding agent to give an w-acyloxyalkylene derivative;

benzene, toluene or xylene in the cyclization reaction 75 an? w-haloalkylene is reacted with a mono alkali metal eg -4am glycol'ate such as mono sodium ethylene. glycolate' by reflu n in an iner solve t uch 1 n n .QI' wh o e an .N' yd xyal l neo'xva k eu dc v rxor an e-halo'alkyl'erie such as o-chloroethylisreacted with an excess of p-hydroxyethyl ether in the presence of'an acid-binding agent in an inert solvent such as benzene or toluene to" give an 'N. hydfoxyethoxyethoxyethyl derivative;-

Th'exend products of this process may be combined with a pharmaceutical carrier for administration to humans in an amount to' attain the' desired pharmacodynamic eifect'. Such carriers are either solidor'liquid. Exemplary of 'solid' pharmaceutical carriers are lactose; cornstarch,-mannito1, talc, etc. The compounds 'of this invention are mixed with the carrier and filled into hard gelatin capsules or tableted with suitable tableting aids such as magnesium.stearate, starch,- or. other lubricants, disintegrants or coloring agents. If 'combinationwitha liquid carrier 'isdesirable, a soft gelatin capsule is filled with av slurry of the novel compounds in soybean or peanut oil. Aqueous suspensions or solutions are prepared for. alternate .oral or parenteral administration; i. The following examples are drawn to illustrate novel compounds ofthis invention and will serve to illustrate procedures for the preparation of the. compounds as well as the utility of Z-trifluoromethylphenoxazine as an intermediate. It will be readil'y'apparent to one skilled in the art that variations of these procedures are possible.

Exantple- 1 g g Example 2 I y A .mixt'ure,v of 261" gLof 2-bromophenol, 340 g'. of 3 nitro:4-chlorobenzotrifluoride and 20 ml. of water is sti'rr'ed while 94 g. of potassium hydroxide is added slow-. 1y for 15 minutes. The mixture is heated at 110-115 (1. 101 three hours. Water 200 ml.) is added. The organic layer is distilled to give 2-nitro 4 trifluor'onrethyl- 2-bromodiphenyl ether.

A mixture of 387 g. of the nitro compound and 475 g. of iron filings'i'n 1750 ml. of water is stirred at reflux temperature for" three hours while 1 l. of glacial acetic acid is gradually added. After refluxing for 3 hours, the mixture" is cooled and thoroughly extracted with benzene. The" residue from the extract 'is 2-amino-4-trifluoromethyl-2-br'omodiphenyl ether; I

' A mixture of61 g. of the amine and 159 g. of 90% formic acid is heated to a liquid temperature of about 160" C. Water and excess formic acid are allowed to distill 01f. The remaining" volatiles are taken 01f the crude Z-tormamidd 4 trifluoromethyl-Z'bromodiphenyl ether by applying a vacuum of20-30 mm. The crude formyl derivative is mixed with 17 g. of potassium carbonate, 1 g. .of c'upric carbonate and 100 ml. of. xylene. The mixture is heated at reflux over a water separator for 20v hours. A- solution of 8 g. of sodium hydroxide in 50ml.- ofiwater is added to the xylene solution of N-formyl-2-trifluoromethylphenoxazine and the mixture is heated'at reflux for two hours. The mixture is diluted A mixtureof 100' gpof 4-chlo'r'o-3-nitrotrifluorornethyl benz ne; 140 g'. of guaiacol, 60 g. potassium hydroxide and 201131. of water is heated at reflux with stirring for three hours; Aft'erl'c'ooling', the" reaction mixturefii's shaken with a' mixture of benzene and dilute alkali solution and Water; After evaporation of the solvent and distillation of the excess nitrocompound, the crude 2'-methoxy-2mitro-4-trifluoromethyldiphenyl ether is ob- Ialne'cl. i U

A solutio'n of 125 g. ofthec'rude diphenyle'th'e'r in 700 ml. of ethanol is treated with 12 g. ofRar ey nickel and 95 7 ml. of hydrazine hydratewith stirring. Thereactio'n mixture'is heated on thejsteain bath for one hour, then filtered through a filter aid The-solvent is evaporated in'vacuo and 500ml. er 48% hydrobro'mic acid added. The acid mixture is then heated for two hours as the vapor temperature climbs to 120-125 C. ,The acid solution is diluted with water; The precipitate'is dissolved in sodium hydroxide solution, washed with ether and recovered by acidification with acetic acid. After filtration, washing with water and drying, Z-amino-Z- hydroxy 4-triiluoromethyldiphehyl ether is obtained. Sixty'grams of this ether are heated with 8.0 ml. of concentrated hydrochloric acid two; Cariu's' tubes at with'w'ater and benzene sufliciently to completely dissblve the. solid. The benzene layer is removed and the residue vacuum distilled to give a 70%. yield of 2-t=riflu'o'r'omethylplieuoxazine- I a V Example? i A suspension of 12,1 g. of 2-trifluoromethylphenox azine and 8.0 g. of potassium amide in 150 ml. of toluene is heated at'reflux withstirring briefly: After the addition. of-1-5.0 g.-of; Sabromo-l-diethylaminopropane hydrobromide the reflux period is continued for six hours. The reaction mixture is; cooled, diluted carefully with water and neutralized. The organic layers are extracted with; dilute hydrochloricacid. The desired-base, 10-(3- diethylaminopropyl) 2' 5 trifiuoromethylphenoxazine, is then isolated by regenerating the base with sodium carbonate and molecularly distilling the'base.

A- solution of 3.4g. of the base'is dissolved-in m1.

' of ethylacetate. A solution of 1.2 g. ofmaleic acid 00? C. for ten hours. .Thesolid disselved'inae'etone,

neutralized with sodium. {bicarbonate and evaporated in vacuo; The residue isthendi stilled byshort passage distillation 'toi-g'ivei a solid distillate which is taken into b'enzene'. Unchanged starting material is recovered by ext acting the benzene solution with dilute sodium: hydroxide solution; Thebenzene layer is dried, concentrated and diluted with hexane to give crystals of 2-trifluoromethylph'eno'xazine. a v g A suspension of 5.0" g. of Z-trifihoromethylphenoxa'zine, g. of. B-chloro-I-dimethylaminopropane and 1.0. ofsodium amide in 30- ml. of benzeneisheated atrefliix. -with stirring for eighthours; The c'ooled mixture i'slquenchedwith 20" ml; of water. 'Thelbenzene layer. is separated and extracted with hydrochloric acid.

qn a-ddition ofcausticito the"aqueous layer, the base' is recovered, and distilled 'with a 'microdistillatioii, short path: apparatus to give 10-(3-dim ethyl aminopropyl)- 2- in; 2.5 m1. oi ethyl acetate isadded. The filtered'solution is evaporated to a low volume diluted somewhat'with ether and cooled to separate 10-(3--diethylamiriopropyl) 2-t1 ifiu'oromethylpl' enioxazine maleate.

7 Example 4 a 'A- suspension Of--4;3 g. of the p-toluenesulphonic acid salt of 3-dimethylaminopropyl-l-p-toluenesulphonate; prepared by the reaction of p-toluenesulphonyl chloride with 1-dimethylamino-3-hydroxypropane in pyridine then forming the salt from the resulting free base, 2.3 g. of sodium Tarriide and 5.0 g. of Z-trifluoromethylphenoxazine illml; of toluene is heated atreflux for three hours. The cooled reaction mixture is washed With Water andex- 'tracted with several portions of dilute hydrochloric acid.

The'acid extracts are then worked up as before to yield the desired 10-.(3-dimethylaminopropyl)-2 trifluoromethyl'phenoxa'zine. V 9

Part of this free base (7-50 mg;) is dissolved in ethanol. The solution is saturated with hydrogen; chloride "gas.

Crystals of 10-(3edimethylaminopropyl)-2-trifluoromethylphenoxazine hydrochloride separate after gradual evap- QIQUOHV on the steambath and trituration with ether.

Example" 5 i A- suspension of.. 12 .5. g. ot'.- 2 -.triiluoromeithylpheuox- 'a zine', 1.4 g. of 3-chloro 2 methyl{l}dimethylaminopropane and 2.0 g. of sodium amide. in m1. of dry '7 benzene is heated at reflux for eight hours. The reaction mixture is diluted with Water, neutralized and the organic layers separated. Vacuum distillation yields (2-methyl-3' dimethylaminopropyl) 2 trifluoromethylphenoxazine.

. Example 6 A mixture of 2.5 g. of 2-trifluoromethylphenoxazine, 0.4 g. of sodium amide and 50 ml. of xylene is stirred and heated at reflux for 20 minutes. A solution'of 1.9 g. of l-(3'-chloropropyl)-4-methylpiperazine in 10 ml. of xylene is added andthe mixture refluxed for several hours. The cooled reaction mixture is heated with Water, extracted with dilute hydrochloric acid and the acid extracts neutralized with aqueous ammonia. Benzene extraction and subsequent removal of the dried solvent in vacuo yields 10-[3-(4-methyl-1"-piperazinyl)-propyl] -2-trifluoromethylphenox azine.

An ethereal solution of the free base is treated with ethereal hydrogen chloride to give the dihydrochloride salt.

Example 7 A suspension of 5.0 g. of 2etrifluoromethylphenoxazine, 0.8 g. of sodium amide and 5.1 g. of N-carbethoxy-N- (3-chloropropyl)-piperazine in 100 ml. of toluene is heated at reflux for four hours. Working up the reac tion mixture as in Example 6 yields 10-[3'-(N-carbethoxypiperazinyl -propyl] 2-trifluoromethylphenoxazine.

A solution of 2.5 g. of the free base in 25 ml. of aqueous ethanol and 1.5 m1. of 40% sodium hydroxide solution is heated at reflux for four hours. The solvent is removed in vacuo and the residue treated With benzene and water. The dried organic layer is evaporated to give the product, 10 (3apiperazinylpropyl)-2-trifluoromethylphenoxazine.

' Example 8 One equivalent of ethylene oxide is added to a solution of 10.0 g. of 10-(3-piperazinylpropyl)-2-trifluoromethylphenoxazine (prepared as in Example 7) in 50 ml. of methanol and the mixture heated at reflux for one and one-half hours. The solvent is removed in vacuo and 4.0 g. of acetyl chloride in 20 ml. of benzene is added to a benzene solution of the residual hydroxyethyl compound. This mixture is refluxed for 20 minutes and solvents are removed in vacuo to give 10[3'-(N-acetoxyethylpiperazinyl)-propyll 2 trifluoromethylphenox: azine hydrochloride. Treating an alcoholic solution of the hydrochloride with isopropanolic hydrogen chloride yields the dihydrochloride salt.

.Similarly, acylating the 10-[3'-(N-hydroxyethylpiperazinyl)-propyll-2-trifluoromethylphenoxazine (prepared as described above) Withbenzoyl chloride furnishes the 10-[3'-(N-benzoyloxyethylpiperazinyl)-propyl] 2 trifluoroinethylphenoxazine hydrochloride which may be converted to the dihydrochloride salt as above.

Example 9 pyl] -2-trifluoromethylphenoxazine.

Example 10 A mixture of 5.0 g. of Z-trifluoromethylphenoxazine, 0.8 g. of sodium amide and 4.2 g. of 1-(3'-chloro-2'- methylpropyl)-4-methylpiperazine in 100 ml. of xylene is stirred and refluxed for'four hours. Working up the cooled reaction mixture as described in Example 6 yields 8 10 [3 (4" methyl 1" piperazinyl) 2' methylpropyl] -2-trifluoromethylphenoxazine.

Reaction of a saturated ethereal solution of tartaric acid with the free base yields the corresponding tartrate salt.

Example 11 A suspension of 7.5 g. of 10-(3'-piperazinylpropyl)-2- trifluoromethylphenoxazine, 5.6 g. of 4-bromo-4'-hydroxybutyl ether (prepared by the careful treatment of 4,4'-dihydroxybutyl ether with one equivalent of hydrobromic acid) and 4.2 g. of potassium carbonate in 150 ml. of xylene is refluxed for 24 hours. Working up the reaction mixture as in Example 11, 10-[3'-(N-hydroxybutoxybutylpiperazinyl) propyl] 2 trifluoromethylphenoxazine is obtained.

Example 13 A solution of 4.2 g. of 10-E3'-(N-hydroxyethylpiperazinyl) -propyl] -2-trifluoromethylphenoxazine (prepared as in Example 8) and 1.9 g. of propionyl chloride in 50 ml. of benzene is heated at reflux for one hour. The

hours.

reaction mixture is cooled and the solvent removed in vacuo. The residue is dissolved in alcohol and treated with isopropanolic hydrogen chloride to give the product, 10 [3' (N propionyloxyethylpiperazinyl) propyl]- Z-trifluoromethylphenoxazine dihydrochloride.

Example 14 A mixture of 7.6 g. of 10-(3-piperazinylpropyl)-2- trifluoromethylphenoxazine, 0.8 g. of sodium amide and 1.8 g. of propyl chloride in ml. of toluene is refluxed for sixrhours. .The cooled reaction mixture is treated with water, extracted with dilute hydrochloricand further worked up as described in Example 6 to give 10-[3'- (4' propyl 1" piperazinyl) propyl] --2 trifluoromethylphenoxazine. V

Treating the free base with anhydrous hydrogen bromide in an ether-alcoholic solution gives, the corresponding dihydrobromide salt.

Example 15 V V A mixture of 24.6 g. of 10- [3'-(N-hydroxyethyl- -piperazinyl) -propyl] -2-trifluoromethylphenoxazine dihydrochloride (prepared by treating the N-hydroxyethyl free base prepared as in Example 8 with an excess of 'isopropanolic hydrogen chloride) and 9.0. g. of thionyl chloride in 200ml. of chloroform is refluxed for five V Thesolvent is removed by evaporation to give a solid, 10- [3 (N-p-chloro ethylpiperazinyl) -propyl] -2- trifluoromethylphenoxazine dihydrochloride. o 'A mixture of 29.6 ml. of fl-hydroxyethylrether and 25 ml. of benzene is heated over an azeotropic trap until '10 ml. of benzene is collected. To the. cooled residue 0.7 g. of sodium is added and refluxing continued until the sodium has disappeared. The dihydrochloridesalt of the chloro intermediate prepared as above (5.1 g.) is added and the mixture is heated and stirred on the'stea'm bath for three hours, allowing the benzene to evaporate.

The residue is stirred at room temperature for 18 hours,

.then quenched with 100 ml. of water. The mixture is :extracted with benzene. The extracts are taken through dilute hydrochloric'acid and. then neutralized to give an ,oil which is extracted into chloroformr The chloroform is removed and the residue dissolved in ethyl acetate siesta are; areas oriiiaiie oats gi ge tafi- (N hydroxyethoxyethoxyethylpiperazinyl) propyl] 52- trifluoromethylphenoxazine dimaleate. Y Example 16 Phenyl chlorocarbonate (1.9 g.) is added to aeoliition at 4.2 ao 1Q:L3%N= yd y h lp p razi ylkpr py l- 'Z triiluorOmethyl henoXaZine (prepared as in Example 9 hy a aar dim w h. ti a d maintaining the temperature at 25-30 C. After. .15 hours, 25 ml. of water is added and the mixture is extracted with chloroform. The washed extracts are dried and concentrated to a residue consisting of the phenylcarbonate of [3' (N hydroxyethylpiperazinynpropyl]-2-trifiuoromethylphenoxazine.

:Awl lt'ionof the-phenylcarbenate obtainedas. abovein 50 ml. of anhydrous ether is added dropwise to 100 ml. inf; liquid ammonia with stirring. After vl tlsl-hours "the reaction mixture is treated with water and extracted with ether. The ether extracts are washed with dilute sodium carbonate solution, dried and. concentrated. in vacuo to give the residual l0-[3-(Ncarbamyloxyethylpiperazinyl) -propyl] -2-trifluoromethylphenoxazine.

The free base is converted to the dihydrochloride salt cooled reaction-.ndXtuIe-L is treated- Withwaten; and the :1:

tolueneelayer is separated. Concentration of the dried toluene-.sqlgtion. in vacuo yields.-10;[3.(=tN.-dimethylearbamyloxyethylpiperazinyl) propyll Z trifluoromethylphenoxazine. n

Treating a solution of the free base in ethyl acetate with excess maleic acid; furnishesgthe dimaleate salt.

Similarly, by employing} 3.2g. of diethylcarbamyl chloride in the above procedure; -l0-[3'-(N-diethylcarbamploxyethylpiperazinyl)-propyl] 2 t-rifiuoromethylphenoxaaine is ohtained. 1 r

E mpl 18,--

- 1T .az elm a iliiaatl0:( m a nx nraar1)- l m fl pme ax nlt apaaz ne :(PBPRM as zmp Of :Mmnmmu W I I =9 1 k6 sa aa t aahaneth lr remtei anfl.- -:.ot. methylformamide. After stirring at 95-9105 C. for six and one-half hours;.thesolntion is' cooled and poured int!) :1. of water. The mixture ismade alkaline with 11% sodium hydroxide and is extractediwith chlor'otorm.

The cmerorerfi'extraasar'"washed with water, dried and filtered. The.s*a1venr-.is..remevedi from the filtrate to iv l-lani en hyl) 24 i adama -malar a phenoxa'z'inyly-prcp u iperazme '200'p.s'.i. ofhydrogm and 100 C. in acetic acid}.. us'ing palladium charcoal as a catalyst. The acetic acid solution is filtered and poured onto water, which:precipitated the 3-trifluoromethylphenoxazine as "glistening platelets, which are dried and used in the alkylation .procedure without further purification. I

Example I '20 A suspension of 5 g. of S-trifluoromethylphenoxazine, ,0-. 1 o o m ami e a 1- a :9 N- ar-be haxy-N' "(3 chloropropyl)-piperazine in 100 ml. of xylene is stirred and heated at reflux for 18 hours. Working up the reaction mixture as in Example 6 yields 10-[3'-(N- carbethoxypiperazinyl) propyl] 3 trifluoromethylphen'o'xazine as the free base.

A- solution of 2.5 g. of the free base in 25 ml. of aqueous ethanol and 1.5 ml. of 40% sodium hydroxide solution-1 is: heated at reflux for four hours. The solvent is removed in vacuo and the residue is treated withbem' zene and water. The dried organic layer is evaporated to give the product, l0-(3'-piperazihylpropyl)-3 trifluoromethylphenoxazine.

The reaction of 10.0 g. of this product and one mole of ethylene oxide, carried out as in Example 8, gives the corresponding product, 10' a [3 (N hydroxyethylpiperazinyl), propyl 3 trifluoromethylphenoxazine. A This application is a continuation-impart of pending application Serial No. 754,131, filed August 1 1, 1 95-83 which isa continuation of application Serial No. 624,- 974, filed November 29, 1956, now abandoned.

What is claimed is:

1. Chemical compounds of the class consisting of a free base and its nontoxic organic and inorganic acid addition'salt's; the free base having the formula:

' in which Z is a member selected" from the group con- A mixture-of 5.3 g. of the nitro derivative prepared 7 Example 19 A mixture of 19.9 g. of N-benzyl-o-aminophenol and 22.6 g. of 4-chloro-3-nitrobenzotrifluoride in 250 ml. ethanol and 100 ml. water is warmed for 15 minutes with 10 ml. of 40% sodium hydroxide. After cooling, the product 10-benzy1-3-trifluoromethylphenoxazine, is separated and subjectedto a catalytic debenzylation at sisting of dimethylamino, diethylamino, N-hydrogen piperazinyl, 'N alkylpiperazinyl, the alkyl moiety having 39111.1. t0. 4, carbon atoms,, N-(o-hydroxyalkyleney piperazi'nyl', N (w -"alkanoyloxyalkylene) piperazinyl, the alkanoyl moiety having from 2 to 4 carbonjat'oms, N (w benzoyloxyalkylene) piperazinyh N 9" (as llydroxyalkyleneoxyalkylene) piperazinyl, N (w hy droxyethoxyethoxyethyl) piperazinyl, (o carbamyloxyalkylene) piperazinyl, N (w dimethylcarba- .11iylcutyalkylene) -,piperazinyl and N- -.(w-diethylcarba myloxylakyl'ene) -'piperazinyl;-and R is a member selected em t e: et ewn is i ez ofahxdr enrand; m t y each of the aforesaid alkylene moieties having from-2am 4 carbon atoms.

'2. 'A chemical compound having the basic structural (EHr-C Hr-CHr-N 3. A chemical compound having the basic structural formula: V

11 12 4. A chemical compound having the basic structural .9.v A chemical compound havingthe basic structural formula: formula:

v 6 7N CF V V w j N CFs a cm-cHr-cmqv /Nalkylene-hydroxy (groin-(Edi V r V V 10 10. A chemical compound having the basic structural in which the alkylene moiety has 2 to 4 carbon atoms. formula: v

( JHr-CHPCH N N -oH,cH, -o-oH,cH,-o--oH,cE,-0H

5. A chemical compound having the basic structural 11. A chemical compound having the basic structural formula: 20 V V I I I lam CF:

CHr-CHr-CHzm-N N-CHaCHr-OH cm-oHr-cm-N N-CHaOHz-O-CONH: f 6. A chemical compound having the basic structural A chemical compound having the basic strucmal,

cm a:

formula:

so O

A 8.5 CHr-CHr-CHr-N V N CHzCHr-NH:

13. A chemical compound having the basic structural H CH CH N N-alkylene-oxy-acyl 2'- 2 5 I w 7 in which the alkylene moiety has 2 to 4 carbon atoms and the acyl moiety is alkanoyl having from 2 to 4 carbon atoms. I 1 formula:

7. A chemical compound having the basic structural o V p 0 7 r V p formula: l i r r 7 J V i I N or.

7 f a l p r V v t 5 References Cited in the file of this patent CH2CH2'CH2N NCHnCH2-O-OOCH1 V UNITED STATESiPATENTS A 8. A chemical compound having the basic structural fi g g- -g 50 2,645,640 7' Charpentier u Julv 1 4,1 19, 53 7 1 2,676,971 Cusic et al. -.27, 1954 FOREIGN PATENTS 1 I: m V p 7 201,628 Australia Oct. 20, 1955 GHz HaGHz-N /Nalky1ene-oxy-alkylena-hydroxy 55 03,301 Germany Mar. 12, 1897 OTHER REFERENCES in which each of the alkylene moieties has 2 to 4, carbon ,7 v v 4 Massie: Chem. Reviews, vol. 54, p. 823 (1954).

atoms. 

1. CHEMICAL COMPOUNDS OF THE CLASS CONSISTING OF A FREE BASE AND ITS NONTOXIC ORGANIC AND INORGANIC ACID ADDITION SALTS, THE FREE BASE HAVING THE FORMULA: 